The present invention, in some embodiments thereof, relates to novel derivatives of diphenylamine and their use in the treatment of various pathologies, including pathologies related to potassium ion flux through voltage-dependent potassium channels and/or cortical and peripheral neuron activity, and pathologies related to TRPV1.
Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride ions, into and out of cells. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive and epithelial tissue, and affect a variety of fundamental biological processes. Upon opening of potassium channels, the outward flow of potassium ions makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands and ATP-sensitivity.
The physiologic M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane excitability by being the only sustained current in the range of action potential initiation. Modulation of M-current has dramatic effects on neuronal excitability. It can be modulated by a large array of receptor types, and the modulation can occur either by suppression (deactivation, blocking) or enhancement (activation, opening). Channels enabling M-current flow are often referred to herein and in the art as M-channels.
Potassium channels have been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport. Modulators of potassium channels are therefore prime pharmaceutical candidates, and the development of new modulators as therapeutic agents is an on-going research effort.
Potassium channels modulators are divided to channel-openers and channel-blockers. A potassium channel opener that has gained much attention is retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester). Retigabine is highly selective for KCNQ-type potassium channels consisting of the subunits KCNQ2 and KCNQ3, which was first described in 1993 in EP0554543. Use of retigabine for treating neuropathic pain was disclosed in, for example, U.S. Pat. No. 6,117,900 and EP1223927. Compounds related to retigabine have also been proposed for use as potassium channel modulators, see, for example U.S. patent application Ser. No. 10/022,579 and U.S. Pat. No. 6,472,165.
Other KCNQ potassium channel modulators have been described in, for example, U.S. patent application Ser. No. 10/075,521, which teaches 2,4-disubstituted pyrimidine-5-carboxamide derivatives as KCNQ potassium channel modulator; U.S. patent application Ser. No. 10/160,582, which teaches cinamide derivatives as KCNQ potassium channel modulators; U.S. Pat. No. 5,565,483 and U.S. patent application Ser. Nos. 10/312,123, 10/075,703 and 10/075,522, which teach 3-substituted oxindole derivatives as KCNQ potassium channel modulators; U.S. Pat. No. 5,384,330, which teaches 1,2,4-triamino-benzene derivatives as KCNQ potassium channel modulators; and U.S. Pat. No. 6,593,349 which teaches bisarylamines derivatives as KCNQ potassium channel modulators. U.S. Pat. No. 6,291,442 teaches compounds comprising two or three aromatic rings having a free carboxyl or a carboxyl being linked, via an ester bond, to a lower alkyl ester, attached to one of the rings, for the modulation of Shaker class of voltage gated potassium channels.
It has been shown that two chemically-related non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac and meclofenamic acid, exhibit potassium channel modulation activity as openers of Kv7.2/3 (KCNQ2/3) channels [1], and further have been shown to underlie the neuronal M-currents of these so called M-channels. Pharmacological targeting of M-channels is of great clinical importance. While openers of these channels demonstrate a therapeutic potential for the treatment of neuronal hyperexcitability like migraine, epilepsy and neuropathic pain, blockers of these channels are potentially useful for the treatment of memory deficits and Alzheimer's disease[2, 3].
Derivatives of such NSAIDs have been studied as M-channels modulator. WO2004/035037 and U.S. Patent Application No. 20050250833, which are incorporated by reference as if fully set forth herein, teach derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel openers, especially voltage-dependent potassium channels such as KCNQ2 channel, KCNQ3 channels and KCNQ2/3 channels, as well as neuron activity modulators.
Transient receptor potential vanilloid type 1 (TRPV1) receptor is a ligand-gated non-selective cation channel activated by heat (typically above 43° C.), low pH (<6) and endogenous lipid molecules such as anandamide, N-arachidonoyl-dopamine, N-acyl-dopamines and products of lipoxygenases (e.g., 12- and 15-(S)-HPETE) termed endovanilloids. Apart from peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is expressed throughout the brain. Recent evidence shows that TRPV1 receptor stimulation by endocannabinoids or by capsaicin leads to analgesia and this effect is associated with glutamate increase and the activation of OFF cell population in the rostral ventromedial medulla (RVM).
TRPV1 has also been found to be involved in the regulation of body temperature, anxiety and mediation of long term depression (LTD) in the hippocampus. TRPV1 channels are also located on sensory afferents which innervate the bladder. Inhibition of TRPV1 has been shown to ameliorate urinary incontinence symptoms.
TRPV1 modulators have been described in, for example, WO 2007/054480, which teaches the effect of 2-(benzimidazol-1-yl)-acetamide derivatives in the treatment of TRPV1 related diseases. WO 2008/079683 teaches compounds being a conjugated two ring system of cyclohexyl and phenyl for inhibiting TRPV1 receptor. EP01939173 teaches O-substituted-dibenzyl urea- or thiourea-derivatives as TRPV1 receptor antagonists. WO 2008/076752 teaches benzoimidazole compounds as potent TRPV1 modulators and EP01908753 teaches TRPV1 modulators being heterocyclidene acetamide derivatives.